Combination Therapy Better Than Monotherapy for Children With Type 2 Diabetes

Daniel Weiss, Senior Editor

Published Online: Tuesday, May 8, 2012

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In a clinical trial, a combination of 2 drugs performed better than a single drug or a drug plus lifestyle intervention for children with type 2 diabetes.
Metformin plus rosiglitazone is more successful at achieving glycemic control in children with recent-onset type 2 diabetes than metformin alone or metformin plus intensive lifestyle intervention, according to a study published in the April 29, 2012, issue of the New England Journal of Medicine. All 3 treatments had disturbingly high failure rates, however, underscoring the need to find more effective means of treating type 2 diabetes in children, which is growing increasingly common.

The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, a multicenter randomized clinical trial, included 699 participants between the ages of 10 and 17 who had had type 2 diabetes for less than 2 years and a body mass index (BMI) at or above the 85th percentile. Enrollment spanned from July 2004 to February 2009, with follow-up continuing until February 2011 for a minimum follow-up of 2 years. On average, participants had had diabetes for 7.8 months at enrollment, and the mean follow-up was 3.8 years.

Participants received one of 3 treatments: metformin alone (1000 mg twice per day), metformin plus rosiglitazone (4 mg twice per day), or metformin plus intensive lifestyle intervention geared toward weight loss through changes in diet and activity. 32.5% of participants were non-Hispanic blacks, 39.7% were Hispanics, and 20.3% were non-Hispanic whites. At enrollment, participants had a mean A1C of 8.0%.

In all, 45.6% of participants reached treatment failure, defined as an A1C persistently above 8.0% for 6 months or persistent metabolic decompensation, including 51.7% of the monotherapy group, 38.6% of the combination therapy group, and 46.6% of the metformin plus lifestyle intervention group. Metformin plus rosiglitazone was associated with a statistically significant 25.4% decrease in treatment failure compared with metformin alone. The treatment failure rate of metformin plus lifestyle intervention did not differ significantly from that of either the monotherapy group or the combination therapy group.

The metformin plus rosiglitazone group had the greatest increase in BMI, followed by the metformin-only group and the metformin plus lifestyle intervention group. The average change in percent overweight after 6 months of treatment was 0.81% for metformin plus rosiglitazone, -1.42% for metformin alone, and -3.64% for metformin plus lifestyle intervention. At 24 months, the corresponding numbers were 0.89%, -4.42%, and -5.02%. The portion of patients with a reduction of at least 7 percentage points in percent overweight in the metformin plus rosiglitazone group was 16.7%, compared with 24.3% for the metformin-only group and 31.2% for the metformin plus lifestyle group. However, neither BMI at baseline nor change in BMI over time was a determinant of treatment failure.

The overall treatment failure rate was 44.3% for girls and 48.2% for boys. Metformin plus rosiglitazone was more effective in girls than in boys and was significantly more effective in girls than the other treatment options, whereas for boys it was not significantly more effective than the other treatment options. The overall treatment failure rate was 52.8% for non-Hispanic blacks, 45.0% for Hispanics, and 36.6% for non-Hispanic whites. Serious adverse events were experienced by 19.2% of participants—18.1% in the monotherapy group, 14.6% in the combination therapy group, and 24.8% in the metformin plus lifestyle intervention group.

The researchers note that the trial’s results include a number of findings that will require further investigation. First, the failure rate of metformin alone was higher than in similar cohorts of adults treated with metformin monotherapy, and further analysis will be necessary to determine whether this is due to biologic or pathophysiological differences between adults and children or both. Second, it is unclear whether the superior performance of combination therapy was specifically due to use of rosiglitazone, a general effect of thiazolidinediones, or a product of combining the 2 drugs. Piecing out the latter will be particularly important given that use of rosiglitazone is restricted by the FDA due to an association with increased risk of heart attack and stroke in adults.

The search for an effective treatment for children with type 2 diabetes is increasingly important given the growth in the number of cases in this age group. As an accompanying editorial notes, the portion of new-onset cases of diabetes among adolescents that are type 2 has increased from 3% a few decades ago to 50% today.

To read the study, click here. To read the accompanying editorial, click here. (Registration may be required for access to full text.)

In his keynote address at the American Pharmacists Association’s general session, Daniel Kraft, MD, chairman of the medicine and neuroscience tracks for Singularity University, posited that it is time to think outside the box and reimagine health and pharmacy.